Methods and formulations for the delivery of pharmacologically active agents

ABSTRACT

In accordance with the present invention, novel formulations have been developed which are much more effective for the delivery of hydrophobic drugs to patients in need thereof than are prior art formulations. Invention formulations are capable of delivering more drug in shorter periods of time, with reduced side effects caused by the pharmaceutical carrier employed for delivery.

RELATED APPLICATIONS

The present application is a continuation of U.S. Ser. No. 11/240,940,filed Sep. 29, 2005, now pending, which is a continuation of U.S. Ser.No. 10/146,706, filed May 14, 2002, now abandoned, which is acontinuation-in-part of U.S. Ser. No. 09/628,388, filed Aug. 1, 2000,now issued U.S. Pat. No. 6,506,405, which is a divisional of U.S. Ser.No. 08/926,155, filed Sep. 9, 1997, now issued as U.S. Pat. No.6,096,331, which is a continuation-in-part of U.S. Ser. No. 08/720,756,filed Oct. 1, 1996, now issued as U.S. Pat. No. 5,916,596, and U.S. Ser.No. 08/485,448, filed Jun. 7, 1995, now U.S. Pat. No. 5,665,382, whichis, in turn, a continuation-in-part of U.S. Ser. No. 08/200,235, filedFeb. 22, 1994, now issued as U.S. Pat. No. 5,498,421, which is, in turn,a continuation-in-part of U.S. Ser. No. 08/023,698, filed Feb. 22, 1993,now issued as U.S. Pat. No. 5,439,686 and U.S. Ser. No. 08/035,150,filed Mar. 26, 1993, now issued as U.S. Pat. No. 5,362,478, the contentof each of which are hereby incorporated by reference therein in theirentirety.

FIELD OF THE INVENTION

The present invention relates to novel formulations of pharmacologicallyactive agents and methods for the delivery of such agents to subjects inneed thereof.

BACKGROUND OF THE INVENTION

In the quest for next generation therapies to treat cancer, scientistoften discover promising compounds only to find that the molecule ishighly insoluble in water, and hence impossible to deliverintravenously. Such was the problem with paclitaxel, an extremelyeffective anti-tumor agent discovered over a quarter century ago by theNation Cancer Institute. Despite almost 30 years of effort, the onlymethod currently approved to address this problem of water-insolubilityof paclitaxel is the use of a toxic solvent (cremophor) to dissolve thedrug, and administer this solvent-paclitaxel mixture over many hoursusing specialized intra-venous tubing sets to prevent the leaching ofplasticizers. This solvent-drug mixture, currently marketed in brandedand generic forms, has become the most widely used anti-cancer agent asit has shown activity in breast, lung and ovarian cancer and isundergoing multiple clinical trials exploring its application incombination with other drugs for other solid tumors.

The cremophor formulation of paclitaxel is associated with significantside-effects including life-threatening allergic reactions requiring theneed for steroid pre-treatment for every patient receiving the drug, andsevere infections as a result of lowering of white blood cells requiringthe need for expensive blood cell growth factors. Ultimately thesetoxicities result in dose-limitation of cremophor-based paclitaxelformulations, thus limiting the full potential of the very effectivepaclitaxel molecule.

While the above toxic side effects of cremophor paclitaxel formulationsare well known, it has not been widely recognized by scientists in thefield that the presence of cremophor creates a more serious impedimentto realizing the maximal potential of paclitaxel by entrappingpaclitaxel within the hydrophobic cores of cremophor micelles withinmicrodroplets in the blood-stream. The entrapment effect of cremophor isdependent on cremophor concentration. Thus, increasing the doses ofcremophor solutions of paclitaxel can potentially worsen the entrapmentby raising the concentration of cremophor, leading to higher toxicitiesbut none of the potential benefits of higher doses of paclitaxel, sincemuch of the active molecule is unavailable to the intra-cellular space,where it is needed to act.

This entrapment of paclitaxel by cremophor has a profound effect on theintra-cellular availability of the active molecule and hence may havesignificant clinical implications in terms of clinical outcome.Accordingly, there is a need in the art for new formulations for thedelivery of substantially water insoluble pharmacologically activeagents, such as paclitaxel, which do not suffer from the drawbacks ofcremophor.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, novel formulations have beendeveloped which are much more effective for the delivery of hydrophobicdrugs to patients in need thereof than are prior art formulations.Invention formulations are capable of delivering more drug in shorterperiods of time, with reduced side effects caused by the pharmaceuticalcarrier employed for delivery.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 collectively compares the plasma kinetics of radiolabelledpaclitaxel when administered to a mouse model as part of a Taxolformulation (closed squares) or as part of in invention formulation(diamonds; ABI-007). FIG. 1A indicates plasma radioactivity measured upto 0.5 hours after administration. FIG. 1B indicates plasmaradioactivity measured up to 24 hours after administration. Inspectionof the figure reveals that 2-5 fold higher levels of paclitaxel areretained in the plasma up to 3 hours after administration whenpaclitaxel is administered in a cremophor-based formulation (Taxol). Dueto the reduced rate of metabolism for ABI-007, plasma levels ofpaclitaxel are higher after 8 hours when administered in an inventionformulation, relative to a cremophor-based formulation.

FIG. 2 compares the partitioning of paclitaxel between red blood cellsand plasma when administered to a mouse model as part of a Taxolformulation (closed squares) or as part of in invention formulation(diamonds; ABI-007). Inspection of the figure reveals that theblood/plasma ratio for paclitaxel administered as part of acremophor-based formulation (Taxol) in the first 3 hours afteradministration is about 1.5-2, indicating that the majority ofpaclitaxel is retained in the plasma due to micellar formation withcremophor. In addition, it is seen that paclitaxel in a cremophor-basedformulation does not significantly partition into the red blood cells.In contrast, paclitaxel administered as part of an invention formulationreadily partitions into the red blood cells.

FIG. 3 summarizes tumor/plasma partitioning kinetics of paclitaxel whenadministered to a mouse model as part of a Taxol formulation (closedsquares) or as part of in invention formulation (diamonds; ABI-007). Itis seen that the tumor/plasma ratio of paclitaxel increasessignificantly over the first 3 hours when as part of an inventionformulation, as opposed to a Taxol formulation.

FIG. 4 compares the response of mammary carcinoma in a mouse model toexposure to ABI-007 or Taxol.

FIG. 5 compares the response of ovarian carcinoma in a mouse model toexposure to ABI-007 or Taxol.

FIG. 6 compares the response of prostate tumors in a mouse model toexposure to ABI-007 or Taxol.

FIG. 7 compares the response of colon tumors in a mouse model toexposure to ABI-007 or Taxol.

FIG. 8 compares the response of lung tumors in a mouse model to exposureto ABI-007 or Taxol.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there are provided methods forthe delivery of a substantially water insoluble pharmacologically activeagent to a subject in need thereof, said method comprising combiningsaid agent with an effective amount of a pharmaceutically acceptablecarrier which is substantially free of micelle-forming components, andadministering an effective amount of said combination to said subject.

As readily recognized by those of skill in the art, a wide variety ofpharmacologically active agents are contemplated for use in the practiceof the present invention. A presently preferred agent contemplated foruse herein is paclitaxel.

Pharmaceutically acceptable carriers contemplated for use in thepractice of the present invention are biocompatible materials such asalbumin.

Micelle-forming components which are preferably avoided in the practiceof the present invention are surface active materials which are commonlyused to assist in solubilizing substantially insoluble compounds inaqueous media, such as, for example, cremophor.

Invention combination of active agent and pharmaceutically acceptablecarrier can be administered in a variety of ways, such as, for example,by oral, intravenous, subcutaneous, intraperitoneal, intrathecal,intramuscular, intracranial, inhalational, topical, transdermal, rectal,or pessary routes of administration, and the like.

In accordance with another embodiment of the present invention, thereare provided methods to reduce entrapment of a substantially waterinsoluble pharmacologically active agent in vehicle employed fordelivery thereof, said method comprising combining said agent with apharmaceutically acceptable carrier which is substantially free ofmicelle-forming components prior to delivery thereof.

Presently preferred pharmaceutically acceptable carriers contemplatedfor use herein are those having substantially lower affinity for saidagent than does the micelle-forming component. Thus, for example, whilecremophor has the benefit of aiding in the solubilization of agent, ithas the disadvantage of having a substantial affinity for the agent, sothat release of the agent from the carrier becomes a limitation on thebioavailability of the agent. In contrast, carriers contemplated herein,such as, for example, albumin, readily release the active agent to theactive site and are thus much more effective for treatment of a varietyof conditions.

In accordance with yet another embodiment of the present invention,there are provided methods to reduce entrapment of a substantially waterinsoluble pharmacologically active agent in vehicle employed fordelivery thereof, said method comprising employing pharmaceuticallyacceptable carriers which are substantially free of micelle-formingcomponents in aqueous media as the vehicle for delivery of said agent.

In accordance with still another embodiment of the present invention,there are provided methods to prolong exposure of a subject to asubstantially water insoluble pharmacologically active agent uponadministration thereof to a subject in need thereof, said methodcomprising combining said agent with pharmaceutically acceptablecarrier(s) which is (are) substantially free of micelle-formingcomponents prior to delivery thereof.

In accordance with a further embodiment of the present invention, thereare provided methods to facilitate transport of a substantially waterinsoluble pharmacologically active agent across cell membranes uponadministration thereof to a subject in need thereof, said methodcomprising combining said agent with pharmaceutically acceptablecarrier(s) which is (are) substantially free of micelle-formingcomponents prior to delivery thereof.

In accordance with a still further embodiment of the present invention,there are provided methods to facilitate transport of a substantiallywater insoluble pharmacologically active agent into the cellularcompartment upon administration thereof to a subject in need thereof,said method comprising combining said agent with pharmaceuticallyacceptable carrier(s) which is (are) substantially free ofmicelle-forming components prior to delivery thereof.

In accordance with another embodiment of the present invention, thereare provided formulations comprising a substantially water insolublepharmacologically active agent and a pharmaceutically acceptable carrierwhich is substantially free of micelle-forming components, wherein saidformulation provides a higher concentration of said agent in thecellular compartment than a formulation of the same agent with amicelle-forming component.

In accordance with yet another embodiment of the present invention,there are provided formulations comprising a substantially waterinsoluble pharmacologically active agent and a pharmaceuticallyacceptable carrier which is substantially free of micelle-formingcomponents, wherein said formulation provides increased intra-cellularavailability of said agent relative to a formulation of the same agentwith a micelle-forming component.

In accordance with still another embodiment of the present invention,there are provided formulations comprising a substantially waterinsoluble pharmacologically active agent and a pharmaceuticallyacceptable carrier which is substantially free of micelle-formingcomponents, wherein said formulation provides prolonged activity of saidagent relative to a formulation of the same agent with a micelle-formingcomponent.

In accordance with a further embodiment of the present invention, thereare provided formulations comprising a substantially water insolublepharmacologically active agent and a pharmaceutically acceptable carrierwhich is substantially free of micelle-forming components, wherein saidformulation facilitates delivery of said agent to red blood cells.

In accordance with another embodiment of the present invention, thereare provided formulations comprising a substantially water insolublepharmacologically active agent and a pharmaceutically acceptable carrierwhich is substantially free of micelle-forming components, wherein saidformulation releases a portion of said agent contained therein to thelipid membrane of a cell.

In accordance with yet another embodiment of the present invention,there are provided formulations comprising a substantially waterinsoluble pharmacologically active agent and a pharmaceuticallyacceptable carrier which is substantially free of micelle-formingcomponents, wherein said formulation provides reduced levels of saidagent in the bloodstream relative to a formulation of the same agentwith a micelle-forming component.

In accordance with still another embodiment of the present invention,there are provided formulations comprising a substantially waterinsoluble pharmacologically active agent and a pharmaceuticallyacceptable carrier which is substantially free of micelle-formingcomponents, wherein said formulation delivers said agent to thebloodstream over an extended period of time relative to a formulation ofthe same agent with a micelle-forming component.

In accordance with a further embodiment of the present invention, thereare provided formulations comprising a substantially water insolublepharmacologically active agent and a pharmaceutically acceptable carrierwhich is substantially free of micelle-forming components, wherein therate of metabolism of said agent in said formulation is reduced relativeto the rate of metabolism of said agent in a formulation with amicelle-forming component.

In accordance with another embodiment of the present invention, thereare provided formulations comprising a substantially water insolublepharmacologically active agent and a pharmaceutically acceptable carrierwhich is substantially free of micelle-forming components, wherein saidagent has a longer half life in said formulation relative to the halflife of said agent in a formulation with a micelle-forming component.

In accordance with yet another embodiment of the present invention,there are provided formulations comprising a substantially waterinsoluble pharmacologically active agent and a pharmaceuticallyacceptable carrier which is substantially free of micelle-formingcomponents, wherein said formulation provides a higher red bloodcell/plasma ratio of said agent than does a formulation of the sameagent with a micelle-forming component.

In accordance with still another embodiment of the present invention,there are provided formulations comprising a substantially waterinsoluble pharmacologically active agent and a pharmaceuticallyacceptable carrier which is substantially free of micelle-formingcomponents, wherein said formulation provides a higher tumor/plasmaratio of said agent than does a formulation of the same agent with amicelle-forming component.

In accordance with a further embodiment of the present invention, thereare provided formulations comprising a substantially water insolublepharmacologically active agent and a pharmaceutically acceptable carrierwhich is substantially free of micelle-forming components, wherein thearea under the curve for delivery of said agent to a tumor via saidformulation is higher than the area under the curve for delivery of saidagent to a tumor via a formulation of the same agent with amicelle-forming component.

In accordance with a still further embodiment of the present invention,there are provided formulations comprising a substantially waterinsoluble pharmacologically active agent and a pharmaceuticallyacceptable carrier which is substantially free of micelle-formingcomponents, wherein said formulation provides a higher concentrationmaximum (C_(max)) for said agent in tumor cells than does a formulationof the same agent with a micelle-forming component.

In accordance with another embodiment of the present invention, thereare provided formulations comprising a substantially water insolublepharmacologically active agent and a pharmaceutically acceptable carrierwhich is substantially free of micelle-forming components, wherein saidformulation provides a lower concentration maximum (C_(max)) for saidagent in plasma than does a formulation of the same agent with amicelle-forming component.

In accordance with still another embodiment of the present invention,there are provided formulations comprising a substantially waterinsoluble pharmacologically active agent and a pharmaceuticallyacceptable carrier which is substantially free of micelle-formingcomponents, wherein said formulation provides more rapid uptake of saidagent by tumor cells than does a formulation of the same agent with amicelle-forming component.

In accordance with yet another embodiment of the present invention,there are provided formulations comprising a substantially waterinsoluble pharmacologically active agent and a pharmaceuticallyacceptable carrier which is substantially free of micelle-formingcomponents, wherein said formulation enhances delivery of said agent totissue, relative to a formulation of the same agent with amicelle-forming component.

Tissues contemplated for treatment according to the invention includetumors, peritoneal tissue, bladder tissue, lung tissue, and the like.

ABI-007 is a proprietary, cremophor-free, albumin-based paclitaxelnanoparticle, 1/100^(th) the size of a single red blood cell. Based onseveral Phase I studies, it has been shown that ABI-007 can beadministered rapidly without the need for steroid pre-treatment andwithout the need for G-CSF at a maximum tolerated dose of 300 mg/m²given every 3 weeks. This is a significantly higher dose than isapproved for cremophor-based paclitaxel formulations (Taxol) of 175mg/m².

In accordance with the present invention, it has been discovered thatABI-007 acts as a novel biologic nano-transporter for hydrophobic drugssuch as paclitaxel, with the capabilities of rapidly releasingpaclitaxel to the cellular compartment and increasing intra-cellularavailability of the active drug, where it is needed in order to have itschemo-therapeutic effect. Furthermore, through the use of the red bloodcell as a secondary storage vehicle it has been discovered that inaddition to the rapid and increased availability of paclitaxel at theintra-cellullar level, by the recruitment of circulating red bloodcells, ABI-007 further provides a significant prolonged activity of theparent molecule with sustained in-vivo release. These novel mechanismsfor rapid and increased intra-cellular availabilty of the drug at thetumor site, together with sustained trafficking of the non-metabolizedpaclitaxel, has potentially significant implications for the clinicaloutcome in the treatment of solid tumors. Indeed, the pre-clinical andPhase II clinical data presented below supports this notion.

By taking advantage of the differences in binding affinities of albuminand the lipid bi-layer of cell membranes for hydrophobic paclitaxel, thedrug-bearing albumin nanoparticle (ABI-007) would rapidly release aportion of its hydrophobic paclitaxel cargo to the lipid membrane of acell.

In the vascular compartment, the first cell encountered is the red bloodcell. In accordance with the present invention, the red blood cell hasbeen found to rapidly compartmentalize the paclitaxel molecule. Sincethe red blood cell has no nucleus and hence no microtubulin to which thepaclitaxel molecule can bind, nor any degradation machinery within itscore, this cell serves as an ideal secondary storage vehicle for theactive paclitaxel, accounting in part for the prolonged activity ofpaclitaxel noted with ABI-007.

Following partitioning of a portion of its paclitaxel payload to thecirculating red blood cells, the nanoparticle is carried by theblood-stream to the hypervasular tumor, where paclitaxel is rapidlytransferred to the tumor cell-membrane, again due to the differences inbinding affinity. It has been well established by other groups that thehydrostatic pressure within these tumor cells is abnormally higher thanthe surrounding interstitium and vascular space. This abnormally highpressure, together with the fact that the vessels associated with tumorsare also abnormally leaky, creates a barrier to the delivery ofchemotherapeutic agents to the tumor cell. Thus, under thesecircumstances it is imperative that the hydrophobic paclitaxel bereleased rapidly to the lipid cell membrane and be bound by themicrotubules within the nuclues before the drug is ejected from thetumor. Evidence presented herein indicates that ABI-007 provides thatopportunity by the ability to rapidly release the hydrophobic molecule.In contrast, cremophor-based formulations entrap the paclitaxel,limiting the ability of the drug to partition into cells. Thisdifference may have important clinical implications and may account inpart for the positive data noted in the Phase II studies of ABI-007 inmetastatic breast cancer and the evidence for responses in patients whohad previously failed Taxol therapy

As the nanoparticle depeletes itself of paclitaxel into the cellularcompartment within the first 3-8 hours following infusion, the plasmaconcentration of paclitaxel diminshes. At this juncture, paclitaxel(still in its active, non-metabolized form) follows the concentrationgradient and is now transferred to albumin again, and is again carriedto the tumor bed. Thus, a prolonged half-life of paclitaxel has beenachieved, with sustained release and ultimately higher tumorconcentration of the drug.

The invention will now be described in greater detail by reference tothe following non-limiting examples.

Example 1 Preclinical Studies Confirm the Modulation of PaclitaxelRelease by the Protein Nanosphere and Increased Efficacy of Equi-dose ofABI-007 vs Taxol

Using radio labeled paclitaxel, the enahanced intra-cellularavailability of paclitaxel has been confirmed following injection ofABI-007. In addition, the entrapment of Cremophor-bound paclitaxel hasalso been confirmed. This difference in findings correlates with in-vivostudies in mice bearing human breast cancer, with the finding thatABI-007 at equi-dose to Taxol, resulted in improved outcomes that these130 nanometer size particles distributed throughout the body.

Thus, human MX-1 mammary tumor fragments were implanted subcutaneouslyin female athymic mice. Radiolabelled drug was administered when tumorsreached about 500 mm³. Tritium-labelled ABI-007 or tritium-labelledTaxol were administered at a dose of 20 mg/kg. Both groups receivedabout 7-10 μCi/mouse of tritium-labelled paclitaxel. Saline was used asthe diluent for both drugs. At various time points (5 min, 15 min, 30min, 1 hr, 3 hr, 8 hr and 24 hr), 4 animals were sacrificed, then bloodsamples and tumor were recovered for radioactivity assessment.

Radioactivity was determined as nCi/ml of whole blood and plasma, andnCi/g of tumor tissue. Results are presented in FIGS. 1, 2 and 3, andare standardized for radioactivity and paclitaxel dose. The data fromthese studies are also presented in the following tables.

Pharmacokinetic Parameters for Whole-Blood, Plasma and TumorDistribution of ³H-Paclitaxel in ABI-007 vs Taxol

New AUC_(0-inf) AUC₀₋₂₄ (nCi hr/mL or g) (nCi hr/mL or g) C_(max)(nCi/mL or g) Blood Plasma Tumor Blood Plasma Tumor Blood Plasma TumorABI-007 939 1161 5869 ABI-007 656 836 2156 ABI-007 328 473 144 Taxol 8711438 3716 Taxol 849 1415 1804 Taxol 752 1427 117 Ratio 1.08 0.81 1.58Ratio 0.77 0.59 1.20 Ratio 0.44 0.33 1.23 TAXOL: high Plasma AUC -paclitaxel is trapped in cremophor micelles ABI-007: higher Tumor AUC(exposure), pac distributed into cells/tissues ABI-007: Substantiallylower Cmax in Plasma, blood Implies rapid distribution into cells andtissues ABI-007: higher Tumor Cmax - more effective tumor kill

t_(max) (hours) t½_(e) (hours) Vdss (mL/kg) Blood Plasma Tumor BloodPlasma Tumor Blood Plasma Tumor ABI-007 0 0 0.5 ABI-007 17.1 16.1 40.2ABI-007 6939 5180 NA Taxol 0 0 3 Taxol 4.0 3.3 24.1 Taxol 1409 692 NARatio 4.28 4.88 1.67 Ratio 4.92 7.49 ABI-007: Substantially lower tumortmax indicates rapid uptake of paclitaxel into tumor relative to taxolABI-007: Prolonged half life relative to Taxol in blood, plasma andtumor may result in higher antitumor activity ABI-007: Substantiallyhigher volume of distribution indicating extrensive distribution intotissues relative to Taxol

Further studies demonstrate that after 24 hours, the active ingredientof the parent molecule, paclitaxel, remains present in the bloodstream,at double the concentration of Taxol. In studies comparing radiolabelledpaclitaxel in Taxol vs ABI-007, direct measurements reveal increased andprolonged levels of paclitaxel in the tumors of animals receivingABI-007.

Example 2 Toxicity Studies

Toxicity was assessed for Taxol, cremophor and ABI-007. ABI-007 wasfound to be 50-fold less toxic than Taxol, and 30-fold less toxic thanthe cremophor vehicle alone, as illustrated in the following table:

Agent LD₅₀, mg/kg Taxol 9.4 Cremophor 13.7 ABI-007 448.5

Example 3 In vivo Tumor Xenografts

Human tumor fragments were implanted subcutaneously in female athymicmice. Treatment was initiated when tumors reached about 150 mm³. Themice received either CONTROL (saline), ABI-007 (4 dose levels: 13.4, 20,30 and 45 mg/kg) or TAXOL (3 dose levels: 13.4, 20, and 30 mg/kg)administered I.V. daily for 5 days. Saline was used as the diluent forboth drugs.

Determination of Equitoxic dose or MTD: The Equitoxic dose or MTD foreach drug was determined by satisfying one of the following criteria:

-   -   a) Dose for each drug that resulted in similar body weight loss        (≦20%) if no deaths were seen;    -   b) If body weight loss could not be matched, the highest dose at        which no deaths were seen;    -   If neither a) nor b) could be satisfied, the lowest dose that        resulted in similar death rate.

Tumor response to the drugs was compared at the Equitoxic dose or MTDestablished as above. Results for several different tumor types arepresented in FIGS. 4-8.

Example 4 Clinical Studies

i. Entrappment of Paclitaxel By Cremophor

Working independently at Rotterdam Cancer Institute, Dr Alex Sparreboomhas reported in a series of pharmacokinetic studies involving patientsreceiving Taxol that cremophor “causes a profound alteration ofpaclitaxel accumulation in erythrocytes in a concentration-dependantmanner by reducing the free drug fraction available for cellularpartitioning.” He has further found that the drug trapping occurs inmicelles and that these micelles act as the principal carrier ofpaclitaxel in the systemic circulation. Since that publication thesefindings have been independently confirmed by two other groups.

ii. Improved Clinical Activity With ABI-007

Data from Phase II shows both increased effiacacy in metastatic breastcancer patients. When compared to the published literature of responserates to Taxol, the study results showed a dramatic difference in bothresponse rates and time of response as well as evidence of reducedtoxicities associated with ABI-007. Further details can be obtained byreviewing the posters presented at ASCO.

Although the present invention has been described in conjunction withthe embodiments above, it is to be noted that various changes andmodifications are apparent to those who are skilled in the art. Suchchanges and modifications are to be understood as included within thescope of the present invention defined by the appended claims.

That which is claimed is:
 1. A formulation comprising nanoparticlescomprising paclitaxel and albumin which is free of cremophor, whereinthe size of the nanoparticles is in the range of 20-400 nm, and whereinsaid formulation is characterized by one or more of the following:wherein said formulation provides a higher concentration of paclitaxelin the cellular compartment than a formulation of paclitaxel withcremophor; wherein said formulation provides increased intra-cellularavailability of paclitaxel relative to a formulation of paclitaxel withcremophor; wherein said formulation provides a higher concentrationmaximum (Cmax) for paclitaxel in tumor cells than does a formulation ofpaclitaxel with cremophor; wherein said formulation enhances delivery ofpaclitaxel to a tumor tissue relative to a formulation of paclitaxelwith cremophor; and wherein said formulation enhances delivery ofpaclitaxel to pancreas, prostate, kidney, lung, heart, bone, or spleenrelative to a formulation of paclitaxel with cremophor.
 2. Theformulation of claim 1, wherein the albumin is human serum albumin. 3.The formulation of claim 1, wherein said formulation enhances deliveryof paclitaxel to a tumor tissue relative to a formulation of paclitaxelwith cremophor.
 4. The formulation of claim 3, wherein said formulationenhances delivery of paclitaxel to pancreas, kidney, lung, heart, bone,or spleen relative to a formulation of paclitaxel with cremophor.
 5. Aformulation comprising nanoparticles comprising paclitaxel and albuminwhich is free of cremophor, wherein the size of the nanoparticles is inthe range of 20-400 nm, wherein upon administration of said formulationthe area under curve of paclitaxel increases proportionally with thedose of paclitaxel between about 55 mg/m2 and about 158 mg/m2.
 6. Theformulation of claim 5, wherein the albumin is human serum albumin. 7.The formulation of claim 5, wherein upon administration of saidformulation the area under curve of paclitaxel increases proportionallywith the dose of paclitaxel between about 55 mg/m2 and about 700 mg/m2.8. The formulation of claim 5, wherein said administration isintravenous administration.
 9. A method of administration comprisingadministering formulation comprising nanoparticles comprising paclitaxeland albumin which is free of cremophor, wherein the size of thenanoparticles is in the range of 20-400 nm, and wherein said formulationis characterized by one or more of the following: wherein saidformulation provides a higher concentration of paclitaxel in thecellular compartment than a formulation of paclitaxel with cremophor;wherein said formulation provides increased intra-cellular availabilityof paclitaxel relative to a formulation of paclitaxel with cremophor;wherein said formulation provides a higher concentration maximum (Cmax)for paclitaxel in tumor cells than does a formulation of paclitaxel withcremophor; wherein said formulation enhances delivery of paclitaxel to atumor tissue relative to a formulation of paclitaxel with cremophor; andwherein said formulation enhances delivery of paclitaxel to pancreas,prostate, kidney, lung, heart, bone, or spleen relative to a formulationof paclitaxel with cremophor.
 10. The method of claim 9, wherein thealbumin is human serum albumin.
 11. The method of claim 9, wherein saidformulation enhances delivery of paclitaxel to a tumor tissue relativeto a formulation of paclitaxel with cremophor.
 12. The method of claim11, wherein said formulation enhances delivery of paclitaxel topancreas, kidney, lung, heart, bone, or spleen relative to a formulationof paclitaxel with cremophor.
 13. The method of claim 9, wherein saidadministration is intravenous administration.
 14. A method ofadministration comprising administering a formulation comprisingnanoparticles comprising paclitaxel and albumin which is free ofcremophor, wherein the size of the nanoparticles is in the range of20-400 nm, and upon administration of said formulation the area undercurve of paclitaxel increases proportionally with the dose of paclitaxelbetween about 55 mg/m2 and about 158 mg/m2.
 15. The method of claim 14,wherein the albumin is human serum albumin.
 16. The method of claim 14,wherein upon administration of said formulation the area under curve ofpaclitaxel increases proportionally with the dose of paclitaxel betweenabout 55 mg/m2 and about 700 mg/m2.
 17. The method of claim 14, whereinsaid administration is intravenous administration.